or other irinotecan-based regimens Efficacy of FOLFIRI-3 or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study FC Bidard (1), C Tournigand (1), T André (2), M Mabro (3), A Figer (4), A Cervantes (5), G Lledo (6), L Bengrine-Lefevre (1), F Maindrault-Goebel (1), C Louvet (1), A de Gramont (1) aimery.de-gramont@sat.aphp.fr (1) AP-HP, Hôpital Saint Antoine, Paris, France; (2) AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; (3) Hôpital Foch, Suresnes, France; (4) Sourasky Medical Center, Israël; (5) Hospital Clinico Universitario Valencia, Valencia, Spain; (6) Clinique Saint Jean, Lyon, France

Abstract Background: No standard schedule of irinotecan has been established in metastatic colorectal cancer patients after first line oxaliplatin. Methods: In OPTIMOX1 study (first line FOLFOX), irinotecan-based chemotherapy was recommended as second line treatment. Data concerning second line were prospectively registered but evaluation was not centrally monitored. Second line PFS and tumor response were analyzed according to type of irinotecan-based regimen administered. Results: 342 patients received an irinotecan-based second line among the 620 patients enrolled in OPTIMOX1 study: FOLFIRI-3 (n=109), FOLFIRI-1 (n=112), and other various irinotecan-based regimens (n=121). Median second line PFS was 3.0 months. In multivariate analysis, FOLFIRI-3 regimen (RR=0.43, 95%CI=[0.28- 0.68], p=0.0003) and LDH level at inclusion (p=0.0006) in OPTIMOX1 were associated with a longer second line PFS. Conclusions: In unselected patients pretreated with FOLFOX, the PFS of irinotecan-based chemotherapy regimens might be shorter than described in second line trials. PFS in second line was improved by FOLFIRI-3 regimen, compared to the other irinotecan-based chemotherapy regimens.

Background No irinotecan-based regimen has been established as a standard in second line chemotherapy in patients previously treated with FOLFOX. The FOLFIRI-1 regimen [Tournigand JCO 2004] has been recently reported to offer superior activity over two other irinotecan-based regimens (mIFL and CapeIRI) [Fuchs JCO 2007].  However, the FOLFIRI-1 regimen achieved only a 4% response rate with 2.5 months median PFS in FOLFOX pretreated patients (n=111) [Tournigand, JCO 2004]. The FOLFIRI-3 regimen [Mabro, Br J Cancer 2006] takes advantage of irinotecan potentiation by 5FU, with fractionated irinotecan administration.  The FOLFIRI-3 regimen achieved a 23% response rate with 4.7 months median PFS in FOLFOX pretreated patient (n=65) [Mabro, Br J Cancer 2006]. Another group reported a 4.5 months PFS in the same setting (n=27) [Viel, Am J Clin Oncol 2008].

Background: FOLFIRI-1 and FOLFIRI-3 regimens FOLFIRI-1: irinotecan 180 mg/m² on day 1 followed by bolus and continuous 5FU 5FU bolus 400 mg/m² LV 400 mg/m² 120 min 5FU 46-hour continuous infusion 2,000 mg/m² CPT11 180 mg/m² 90 min FOLFIRI-3: double infusion of irinotecan, before and at the end of 5FU infusion LV 400 mg/m² 120 min 5FU 46-hour continuous infusion 2,000 mg/m² CPT11 100 mg/m² 60 min CPT11 100 mg/m² 60 min

Methods In the OPTIMOX1 study (frontline FOLFOX), irinotecan based regimen was mandatory in the second line setting (without randomization). Treatment evaluation was reported by investigators but was not centrally monitored. We have used prospectively registered data in order to compare the efficacy of FOLFIRI-3 to the other irinotecan-based regimens currently used in FOLFOX pretreated metastatic colorectal cancer patients. For the present study based on patients included in the OPTIMOX1 trial Inclusion criterion = irinotecan-based chemotherapy Exclusion criteria = unknown 2nd line PFS, concomitant use of targeted therapy

Results (1) 342 patients have been included in our study. The irinotecan-based regimens were  FOLFIRI-1: n=112 patients (33%)  FOLFIRI-3: n=109 patients (32%)  other irinotecan-based regimens: n=121 patients (35%) Patient characteristics were not different between the three groups  See TABLE 1 Prognostic factors associated with 2nd line PFS were studied  See TABLE 2 PFS curves according to irinotecan-based regimen  See FIGURE 1

Table 1: Patient characteristics All patients FOLFIRI-3 FOLFIRI-1 Others CPT11 P value TOTAL (n) 342 109 112 121 Characteristics before 1st line Age> 60 years 58 % 59 % 62 % 55 % 0.63 Sex: Male 61 % 57 % 63 % 64 % 0.54 PS 1st line > 0 41 % 46 % 39 % 0.53 LDH 1st line > UNL 50 % 56 % 48 % 0.42 ALP 1st line > UNL 47 % 51 % 42 % 0.33 CEA 1st line > UNL 78 % 75 % 77 % 82 % 0.49 1st linePFS<12months 65 % 0.57 Characteristics before 2nd line PS > 0 67 % 0.25 LDH > UNL 70 % 0.27 ALP > UNL 66 % 60 % 0.78

Table 2: Prognostic factors for 2nd line PFS (n=342) Median 2nd line PFS (months) P value univar. P value multiv. RR 95% CI PS 1st line (=before 1st line) 0 vs 1 3.0 vs 2.4 0.02 0.10 1 vs 1.43 0.93-2.18 LDH1st line < vs > UNL 3.5 vs 2.3 <0.0001 0.0006 1 vs 2.38 1.46-3.91 ALP1st line 3.0 vs 2.8 0.06 Not included 1st line PFS < vs >12 mo 2.7 vs 3.2 0.002 0.75 1 vs 0.93 0.60-1.43 PS 2nd line 0/1 vs 2/3 3.0 vs 1.8 0.33 LDH 2nd line < vs >UNL 3.6 vs 3.0 0.005 0.74 1 vs 1.09 0.65-1.82 ALP 2nd line 3.2 vs 2.8 0.68 1 vs 1.1 0.71-1.69 2nd line regimen FOLFIRI 3 3.7 0.0003 1 vs 0.43 0.28-0.68 FOLFIRI 1 (*) 3.0 Other IRI (*) 2.3 (*): FOLFIRI1 and Other IRI were pooled for statistical analysis

Figure 1: 2nd line PFS according to chemotherapy regimen Other Irinotecan based regimen FOLFIRI-3 FOLFIRI-1 , 8 P=0.0017 , 6 Progression-Free Survival (%) , 4 , 2 2 4 6 8 1 1 2 Time (Months)

Results (2) Tumor response (CR & PR) Overall Survival Toxicity 2nd line chemo Response Rate (PR & CR) FOLFIRI 3 17 % FOLFIRI 1 8 % Other IRI-based chemo 6 % All 10 % Tumor response (CR & PR) 301 patients assessed Prognosis factors in multivariate analysis were:  FOLFIRI-3 regimen (p=0.02)  ALP before the 2nd line chemo (p=0.04) Overall Survival 342 patients assessed  LDH before the 1st line chemotherapy (p=0.0005)  ALP before the 2nd line chemotherapy (p=0.048) Toxicity No data were prospectively recorded

Discussion / Conclusion This is an unplanned analysis of the OPTIMOX1 study, using prospectively registered data on 2nd line regimen and its efficacy. This study included unselected patients, and should be the reflect of the everyday management of second line chemotherapy of FOLFOX pretreated colorectal cancers. PFS and Response Rates obtained here by FOLFIRI 3 (3.7 months, n=109) are lower than previously reported in phase II study (4.7 months, n=65) [Mabro, Br J Cancer 2006]. However, FOLFIRI 3 was significantly superior to FOLFIRI 1 and any other irinotecan-based regimen, for both PFS (p=0.0003) and Response Rate (p=0.002). Optimization of chemotherapy regimens is critical, as targeted therapies (bevacizumab, cetuximab) proportionally enhance their antitumor effect [Fuchs, JCO 2007]. FOLFIRI 3 should be further evaluated in randomized phase III trial.